N-Aryl amines and amides are important substructures in natural products and industrial chemicals, such as pharmaceuticals, dyes, and agricultural products. Palladium-catalyzed methods for the N-arylation of amines and amides are now widely-exploited for the synthesis of arylamine and N-arylamide moieties in pharmaceuticals, materials with important electronic properties, and ligands for early metal catalysts. In particular, the palladium-catalyzed reaction of aryl bromides and aryl iodides with primary and secondary amines and amides is a general method employed for the formation of N-aryl amines and N-aryl amides. However, the reaction conditions employed in these palladium-catalyzed reactions are sufficiently harsh, e.g., in terms of reaction time, reaction temperature, or the requirement for the use of strong base, that many functionalized aryl halide or amine or amide reagents are not suitable reactants because their functional groups will undergo undesired reactions, e.g., decomposition, under the reaction conditions. Moreover, aryl chlorides are typically less suitable reactants in these reactions, due to their low reactivity relative to aryl bromides and aryl iodides. Therefore, it would be advantageous to have additional methods for preparing N-aryl amines and N-aryl amides from arylating compounds, such as aryl halides, and amines and amides.
Further, many currently-practiced methods of producing N-aryl compounds are somewhat inefficient or economically unattractive. For example, workers at Tosoh Company reported that catalysts containing the P(t-Bu)3 ligand provided high turnover numbers for the formation of aryl piperazines with excess ligand (4:1 ratio of P(t-Bu)3 to Pd) at 120 C. Nishiyama, N. et al. Tetrahedron Lett. 39:617-620 (1998); and Yamamoto, T. et al. Tetrahedron Lett. 39:2367-2370 (1998). However, the high temperatures required for this reaction scheme make it somewhat unattractive for commercial use. In another example, Hartwig et al. have shown that a sterically hindered alkylphosphine, prepared in one step, allows for room temperature amination of aryl halides, and that another commercially-available, sterically-hindered alkylphosphine allows for the reaction of aryl chlorides with primary alkylamines under mild conditions. Hamann, B. C. and Hartwig, J. F., J. Am. Chem. Soc. 120:7369-7370 (1998). It has also been reported recently that a P,N ligand containing a biphenyl backbone, which is prepared in three steps, generates a catalyst that leads to examples of room temperature amination chemistry with aryl bromides and room temperature Suzuki chemistry with aryl chlorides. Old, D. W. et al. J. Am. Chem. Soc. 120:9722-9723 (1998).
Notably, nucleophilic N-heterocyclic carbenes, i.e., the imidazoline-2-ylidenes (sometimes called imidazol-2-ylidenes) or so-called “phosphine mimics”, have attracted considerable attention as possible alternatives to phosphine ligands in homogeneous catalysis. A primary advantage of these ligands is that an excess of the ligand is not required. It appears that these ligands do not dissociate from the metal center, thereby preventing aggregation of the catalyst to yield the bulk metal. Further, these imidazoline-2-ylidene carbenes appear to be more thermally stable than phosphine ligands.
A small number of publications describe the limited use of carbene ligands of this type in palladium-catalyzed reactions of aryl halides with various nucleophiles, e.g., hydride, amines, and metal amides. See Viciu, M. S. et al. Organometallics 2001, 20, 3607-12; Cheng, J. et al. Org. Lett. 2001, 3, 1371-74; Lee, S. et al. Org. Lett. 2001, 3, 2729-32; Stauffer, S. R. et al. Org. Lett. 2000, 2, 1423-26; Huang, J. et al. Org. Lett. 1999, 1, 1307-09; and published PCT application WO 01/66248. Importantly, the various methods disclosed in these publications are of dubious practical synthetic utility because each of them has an absolute requirement for the use of a strong base at an elevated temperature. As outlined above, an absolute requirement for the use of a strong base at an elevated temperature in a palladium-catalyzed arylation reaction limits the set of reactants that may be used in the reaction due to the limited number of functional groups that are robust to withstand the reaction conditions for the necessary period of time.
Accordingly, a need continues to exist for a general and efficient process of synthesizing N-aryl amines and N-aryl amides from readily available arylating compounds and amines and amides. The discovery and implementation of such a method would simplify the preparation of commercially significant organic N-aryl amines and amides, and would also likely enhance the development of novel polymers and pharmacologically active compounds. The methods of the present invention address that need.